Diabetic Neuropathy

Experimental studies have provided multiple mechanisms for the development of diabetic neuropathy, yet very few findings have been replicated in patients. Hyperglycemia mediated nerve damage may begin very early even prior to overt diabetes as evidenced by several recent studies in patients with impaired glucose tolerance. Polyol pathway abnormalities have been exhaustively explored in animals, but studies in man are limited and inconsistent and hence not surprisingly, clinical trials with aldose reductase inhibitors have consistently failed. Glycation is widespread and may induce a range of structural and functional changes and glycation inhibitors are being actively developed. Both large and small vessel disease have been implicated in diabetic neuropathy and treatment with ACE inhibitors has shown some benefit. Growth factors may be important in maintaining both the vascular and neuronal phenotype. Thus a range of neurotrophic and vascular growth factors have entered phase III clinical trials for human diabetic neuropathy recently.

Studies in animal models and cultured cells provide a conceptual framework for the cause, and potentially, the treatment of diabetic neuropathy (1) (Fig. 1). Each of these putative pathways has been discussed in detail in several other chapters.

Although, experimental evidence in vivo suggests that these paradigms provide a novel basis for research and drug development, limited translational work in patients with diabetes continues to generate much debate and controversy about their relevance to human diabetic neuropathy. This chapter will therefore focus entirely on the changes, which have been reported in man.

Hyperglycemia

The role of even minor and intermittent episodes of hyperglycemia has been explored recently in patients with impaired glucose tolerance (IGT). Thus, 25% of patients with apparent "idiopathic painful neuropathy" and electrodiagnostic evidence of axonal injury with loss of epidermal nerve fibers have been shown to have IGT (2). The

Fig. 1. Pathogenesis of diabetic neuropathy. Factors implicated in the pathogenesis of diabetic neuropathy include the activation of the polyol pathway, the activation of PKC, increased oxidative stress, the impaired n-6 fatty acid metabolism, auto-oxidation of glucose and the formation of advanced glycation end products, and the reduced bioavailability of neurotrophic factors. All these mechanisms are interrelated and can potentiate each other's detrimental effects. Although the exact mechanisms of their action are not well understood, it is currently believed that these factors lead to reduced Na+, K+ ATPase activity and vasoconstriction, reduced endoneurial blood flow, and nerve hypoxia. All these changes initially result in reduced nerve conduction velocity and demyelination with later axonal loss (75).

Fig. 1. Pathogenesis of diabetic neuropathy. Factors implicated in the pathogenesis of diabetic neuropathy include the activation of the polyol pathway, the activation of PKC, increased oxidative stress, the impaired n-6 fatty acid metabolism, auto-oxidation of glucose and the formation of advanced glycation end products, and the reduced bioavailability of neurotrophic factors. All these mechanisms are interrelated and can potentiate each other's detrimental effects. Although the exact mechanisms of their action are not well understood, it is currently believed that these factors lead to reduced Na+, K+ ATPase activity and vasoconstriction, reduced endoneurial blood flow, and nerve hypoxia. All these changes initially result in reduced nerve conduction velocity and demyelination with later axonal loss (75).

neuropathy in patients with IGT appears milder than the neuropathy associated with newly diagnosed diabetes and it may particularly affect the small nerve fibers (3). They have not demonstrated a reduction in sural nerve amplitude or myelinated fiber density (4). However, a recent study has shown a decrease in distal sural conduction velocity in IGT subjects with normal distal and proximal amplitudes and proximal sural sensory conduction velocity, suggestive of distal demyelination (5). Regarding the mechanistic basis for IGT neuropathy a small nerve biopsy study has shown increased expression of the ligand N epsilon-carboxymethyl lysine and the receptor for advanced glycation end products (RAGE) as well as the transcription factor nuclear factor (NF)-kB in the perineurium, epineurial, and endoneurial vessels in subjects with IGT (6).

In patients with predominantly type 2 diabetes, longitudinal data from the Rochester cohort has suggested that the duration and severity of exposure to hyperglycemia are related to the severity of neuropathy (7). Improvement of glycemic control in type 1 diabetes by intensified insulin as in the Diabetes Control and Complications trial (DCCT) (8), pancreatic transplantation (9), or recently with islet cell transplantation (10) improves neuropathy. However, similar results have not been achieved in patients with type 2 diabetes either in the United Kingdom Prospective Diabetes Study (UKPDS) (11), Veterans Affairs Cooperative Study on Glycemic Control and Complication in NIDDM (VACSDM) study (12), or the Steno-2 study (13), suggesting that either hyperglycemia is not the major driving factor for neuropathy in type 2 diabetes, or that other factors such as hypertension or hyperlipidemia might play more important roles.

Polyol Pathway

Animal models consistently demonstrate an association between increased polyol pathway flux and a reduction in nerve conduction velocity (NCV), which can be ameliorated with aldose reductase inhibitors (ARI's) (14,15). In man, perhaps the potential role of the polyol pathway has been oversimplified and oversold. Thus, in patients with diabetes, considerable heterogeneity has been observed in the level of polyol pathway metabolites in different studies (16-19) and subjects with IGT do not demonstrate an elevated nerve sorbitol, suggestive of a glycemic threshold for activation of this pathway (4). Only one study has shown a significant inverse correlation between the levels of nerve sorbitol and myelinated fiber density (19). Although a careful and detailed study using neurophysiology has shown that subjects with diabetes with the T allele of the C-106T polymorphism had lower peroneal, sural, and radial sensory response amplitudes at baseline and a higher decrease in peroneal motor NCV than those with the C-106C genotype (20). It also appears that those at the highest risk of developing the complications are those with a higher set-point for AR activity (21), which may be further modulated by the activity of Sorbitol dehydrogenase (22). Despite the disappointing results in somatic neuropathy of a meta-analysis of 19 randomized ARI trials which demonstrated only a small reduction in decline of median (0.66 m/second) and peroneal (0.53 m/second) motor NCV (23), several other interventional studies have been more positive and suggest there might be a dose response relationship between the degree of AR inhibition and peripheral nerve regeneration (24-26). Furthermore, recently ARI's have been shown to benefit autonomic dysfunction by showing improvements in esophageal dysfunction (27), gastroparesis (28), and left ventricular ejection fraction (29).

Glycation

Glycation induces a range of cellular and subcellular alterations, which have far reaching effects on tissue biology (30). It might affect the function of matrix metallopro-teinase's, their tissue inhibitors -1 and -2, transforming growth factor-P (31), epidermal growth factor induced autophosphorylation, and activation of extra cellular signalregulated kinases (32). Sural nerves obtained from patients with diabetes at amputation demonstrate significantly elevated pentosidine levels in both cytoskeletal and myelin protein (33). In a recent biopsy study of eight patients with diabetes with polyneuropa-thy and proximal neuropathy, advanced glycation end product (AGE) was localized to the endoneurium, perineurium, and microvessels and the intensity of axonal AGE expression correlated with the loss of axons (34). Pyrraline, an AGE, is also increased in postmortem samples of optic nerve from patients with diabetes (35). The RAGE and its

This guide will help millions of people understand this condition so that they can take control of their lives and make informed decisions. The ebook covers information on a vast number of different types of neuropathy. In addition, it will be a useful resource for their families, caregivers, and health care providers.